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Absent-Minded Mice Shed Light on Memory

Boston--A new breed of forgetful mice paddling in a tiny swimming pool in a lab here offers direct confirmation of the reigning theory of how we remember. By erasing the ability to remember from the mice's brains, a feat described in a series of papers in today's issue of the journal Cell and in a recent issue of Science, biologists are learning how molecular changes affect the patterns of electrical activity that memories are made of.

In one set of studies, a team at the Massachusetts Institute of Technology (MIT) led by Nobel Prize-winning biologist Susumu Tonegawa and neuroscientist Matthew Wilson used an exotic new gene-splicing technique to make "knockout" mice lacking a gene that codes for a receptor for a key neurotransmitter, glutamate. Their method allowed them to delete the gene in only one small group of cells in a brain region called the hippocampus. In another paper in Cell and one in the 6 December issue of Science, a team led by neuroscientists Eric Kandel and Mark Mayford of Columbia University and Robert Muller of the State University of New York Downstate Medical Center in Brooklyn selectively enhanced, rather than deleted, a gene for a particular enzyme (called calcium-calmodulin-dependent kinase II or CaMKII) that's thought to play a key role in the electrochemistry of long-term memory storage.

Both manipulations disrupted nerve-cell firing in the hippocampus and impaired the animals' ability to learn their way around mazes. In the MIT experiments, adult knockout mice were much slower than normal littermates in locating a submerged platform on one side of a tiny swimming pool, and less able to remember the platform's position later. Concludes Tonegawa, "These mice were basically incapable of acquiring spatial memory."

The findings lend weight to the prevailing theory linking molecular events in the hippocampus to spatial learning, which says that memories are built by strengthening the signaling between neurons. This is also the first set of experiments to probe memory at all levels, from molecular changes through altered patterns of nerve-cell firing to impaired learning. "It's a dream of neurobiologists to understand some interesting cognitive phenomena like a memory from the molecular level right up through behavior," says neurobiologist Charles Stevens of the Salk Institute in La Jolla, California. "The articles in Cell are a big step in that direction."